My lab is devoted to translational research in hematological cancers, with a particular focus on B-cell malignancies. The goal of my research is to identify novel biological targets for therapeutic applications in order to improve disease control and overcome drug resistance, particularly relating to B-cell receptor (BCR) pathway in lymphoid malignancies.
We have identified MALT1 as a novel target in chronic lymphocytic leukemia (CLL)that can be used to overcome resistance to BTK inhibitors. MALT1, a para-caspase downstream of PLCγ2, is required for BCR-mediated NF-κBactivation. Targeting MALT1 with the small molecule inhibitor MI-2 has been effective in preclinical models of activated B-cell like diffuse large B-cell lymphoma. MALT1 is essential for NF-κB activation and acts downstream of the most common mutations conferring ibrutinib resistance. We, therefore, hypothesized that targeting MALT1 could be a successful strategy to treat CLL following progression on ibrutinib. We characterize the efficacy and downstream effects of targeting MALT1 in CLL in general and specifically against leukemic cells with acquired ibrutinib resistance. We show that MALT1 is constitutively active in CLL and can be effectively inhibited by MI-2 resulting in reduced BCR and NF-κB signaling. Interestingly MALT1, in contrast to ibrutinib, effectively induced apoptosis of CLL, possibly due to decreased Bcl-xL levels. Importantly, MI-2 remained highly effective against CLL cells harboring mutations conferring ibrutinib-resistance. Our results support the clinical development of MALT1 inhibitors in CLL, particularly for ibrutinib-resistant disease.
Ina second project, we have proved direct in vivo evidence of a pathogenic activity for BCR and NF-κB pathways in Mantle Cell Lymphoma (MCL). The efficacy of ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, in MCL contradicts the notion that MCL is a malignancy of naïve B-cells. Ibrutinib inhibits BCR signaling and prevents downstream activation of the canonical NF-κB pathway. However, the role of BCR signaling in MCL remains ill-defined. To interrogate the signaling pathways activated in MCL in vivo, we profiled gene expression in tumor samples concomitantly isolated from blood and lymph nodes. Expressiondata identified upregulation of BCR and NF-κB signaling and tumor proliferation in lymph node-resident MCL cells compared to tumor cells in the blood. Preferential activation of relevant signaling molecules and Ki67 expression in the lymph node confirmed the gene expression data. A subset of leukemic samples had apparent cell-autonomous BCR activation and/or NF-κB signaling. Those samples carried mutations and/or genetic polymorphism in genes encoding pathway-specific regulatory molecules that may confer ibrutinib resistance. We identified a novel somatic mutation in RELA in one patient (the first report of this mutation in cancer) and rare germline variants affecting components of the linear ubiquitin chain assembly complex (LUBAC) in three other patients.
MyNCBI Link: https://www.ncbi.nlm.nih.gov/myncbi/1NakbGjI4HI5A/bibliography/public/
Selected Publications
Keywords/Tags: Lymphoid malignancies, CLL, MCL, B-cell ALL
